A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
JY Kim, Yuntao Bai, Laura A. Jayne, Ralph D. Hector, Avinash K. Persaud, Su Sien Ong, Shreshtha Rojesh, Radhika Raj, Mei Ji He Ho Feng, Sangwoon Chung, Rachel E. Cianciolo, John W. Christman, Moray J. Campbell, David S. Gardner, Sharyn D. Baker, Alex Sparreboom, Rajgopal Govindarajan, Harpreet Singh, Taosheng Chen, Ming Poi, Katalin Suszták, Stuart Cobb, Navjotsingh Pabla
Abstract
Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI.